Asymmetric hydrogenation of dihydrofuroimidazole derivatives

ABSTRACT

A process for the asymmetric hydrogenation of the furoimidazole derivatives of the general formula: ##STR1## wherein R 1  is a protective group, which is cleavable in a known way, and R 2  is hydrogen or a protective group, which is cleavable in a known way, with hydrogen in the presence of a homogeneous catalyst to the corresponding diastereomeric tetrahydrofuroimidazole derivatives of the general formula: ##STR2## The tetrahydrofuroimidazole derivatives of the general formula II are intermediate products for the production of vitamin (+) biotin.

This application is a continuation of U.S. Ser. No. 08/167,362, filed onDec. 16, 1993, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a new process for the asymmetric hydrogenationof the dihydrofuroimidazole derivatives of the general formula: ##STR3##in which R₁ means a protective group which is cleavable in a known wayand R₂ stands for hydrogen or a protective group which is cleavable in aknown way, with hydrogen in the presence of a homogeneous catalyst tothe corresponding diastereomeric tetrahydrofuroimidazole derivatives ofgeneral formula: ##STR4## in which R₁ and R₂ have the above-mentionedmeanings.

2. Background Art

Most known (+) biotin syntheses pursue the aim of dividing suitableprecursors by, for the most part, very costly methods of racemateresolution with, for the most part, very expensive cleaving agents andfurther pursue the (+)-biotin synthesis with the resulting diastereomers(see, e.g., German Patent No. 2,058,248). Then, according to EuropeanPublished Patent Application No. 273,270, the introduction of therelevant optically active centers, meaning the 3aS and 6aR positions ofthe biotin ring structure, was achieved for the first time by anasymmetric hydrogenation of the corresponding dihydrofuroimidazolederivatives with a typical hydrogenation catalyst, such as, rhodium onaluminum oxide. This process was not completely satisfactory because ofthe attainable yield of the desired diastereomer.

BROAD DESCRIPTION OF THE INVENTION

The main objective of the invention is to provide an improved asymmetrichydrogenation process with which the mentioned key step of the biotinsynthesis can be performed with very good diastereo--selectivity withgood yield of the tetrahydrofuroimidazole.

Other objectives and advantages of the invention are set out herein orare obvious herefrom to one skilled in the art.

The objectives and advantages of the invention are achieved by theprocess and compounds of the invention.

The invention involves a process for the asymmetric hydrogenation of thedihydrofuroimidazole derivatives of general formula: ##STR5## wherein R₁is a protective group which is cleavable in a known way and R₂ is ahydrogen or a protective group which is cleavable in a known way withhydrogen in the presence of a homogeneous catalyst to the correspondingdiastereomeric tetrahydrofuroimidazole derivatives of the generalformula: ##STR6## wherein R₁ and R₂ have the above-mentioned meanings.The homogeneous catalysts that are used can be obtained by reaction of aRh complex with a chiral phoshine ligand from the group consisting of:##STR7## wherein Ph is a phenyl group.

The tetrahydrofuroimidazoles of the general formula II are importantintermediate products in the synthesis of (+)-biotin, a vitaminessential for humans, that is also designated vitamin H. Moreover,(+)-biotin is used as a pharmaceutical agent for the treatment ofdermatosis or as a feed additive with growth increasing effect fordomestic animals.

Preferably the protective groups, which are cleavable in a known way, ofR₁ are phenyl-(C₁ -C₆)-alkyl groups, benzyl groups, and naphthyl-(C₁-C₆)-alkyl groups, and the aromatic nuclei of the respective groups areoptionally substituted with one or more substituents from the listingcomposed of (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, hydroxy, halo, amino, (C₁-C₆)-alkylamino and (C₁ -C₆)-dialkylamino. Preferably the protectivegroups, which are cleavable in a known way, of R₂ are (C₁ -C₆)-alkanoylgroups, (C₁ -C₆)-alkoxy-(C₁ -C₆)-alkyl groups, (C₁ -C₆)-alkoxycarbonylgroups, aroyl groups and benzyl, and the aromatic nuclei of therespective groups are optionally substituted with one or moresubstituents from the listing composed of (C₁ -C₆)-alkyl, (C₁-C₆)-alkoxy, hydroxy, halo, amino, (C₁ -C₆)-alkylamino and (C₁-C₆)-dialkylamino. Preferably the (-)-DIOP ligand or the (S,S)-PNNPligand is used as the chiral phosphine legand in the catalyst.Preferably Rh complexes of the general formula:

    Rh(O): [Rh(L)A].sub.2                                      V

or

    Rh(+): [Rh(L).sub.2 ]B.sup.-                               VI

wherein L stands for two C₂ -C₁₂ olefins or a C₅ -C₁₂ -diene, Arepresents a halogen and B⁻ is an anion of an oxygen acid or complexacid, are used as the catalyst. Preferably the reaction takes place at ahydrogen pressure of 1 to 200 bars and a reaction temperature of 25° to150° C. Preferably the amount of catalyst, expressed as a ratio ofdihydrofuroimidazole to homogeneous catalyst, ranges between 100:1 and5000:1. Preferably aprotic solvents are used, and preferably the aproticsolvent is toluene.

The invention also involves (3aS-6aR)-tetrahydrofuroimidazolederivatives of general formula II wherein R1 is a phenyl(C₁ -C₆)-alkylgroup, whose aromatic nucleus is substituted with one or moresubstituents from the listing composed of (C₁ -C₆)-alkyl, (C₁-C₆)-alkoxy, hydroxy, halo, amino, (C₁ -C₆)-alkylamino, and (C₁-C₆)-dialkylamino, or R₁ is a naphthyl-(C₁ -C₆)-alkyl group, whosearomatic nuclei are optionally substituted with one or more of theabove-mentioned substituents. Preferably R₁ in the(3aS-6aR)-tetrahydrofuroimidazole derivatives is an (R) or(S)-1-phenylethyl group or an (R) or (S)-1-naphthylethyl group.

DETAILED DESCRIPTION OF THE INVENTION

The dihydrofuroimidazoles of the general formula I can be producedaccording to the disclosure and instructions of European PublishedPatent Application Nos. 273,270 and 270,076, and U.S. Pat. Nos.5,162,540, 4,876,350 and 4,851,540.

Suitably the following groups are used as the protective groups, whichare cleavable in a known way, of R₁ : A phenyl-(C₁ -C₆)-alkyl group, abenzyl group or a naphthyl-(C₁ -C₆)-alkyl group; their aromatic nucleican be optionally substituted with one or more substituents from thelisting composed of (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, hydroxy, halo,amino, (C₁ -C₆)-alkylamino, (C₁ -C₆)-dialkylamino. Halo herein can bechloro, bromo, iodo or fluoro. The phenyl-(C₁ -C₆)-alkyl group or thenaphthyl-(C₁ -C₆)-alkyl group can have a chiral center. R₁ preferably isan (R) or (S)-iphenylethyl group, a benzyl group or an (R) or(S)-1-naphthylethyl group, and the aromatic nuclei of the preferredgroups can be substituted with the above-mentioned substituents.

R₂ suitably is a hydrogen or a protective group, which is cleavable in aknown way, selected from the group composed of the (C₁ -C₆)-alkanoyl,benzyl, (C₁ -C₆)-alkoxy, (C₁ -C₆)-alkoxycarbonyl and aroyl, such as,benzoyl; the aromatic nucleus of the benzyl group or the aroyl groupscan be substituted corresponding to the aromatic nucleus of R₁. R₂preferably is acetyl, benzyl, (C_(-C) ₂)-alkoxy-(C₁ -C₂)-alkyl, (C₁-C₂)-alkoxycarbonyl or benzoyl.

It was found that surprisingly homogeneous catalysts that can beobtained by reaction of an Rh complex with a chiral phosphine ligandfrom the series of: ##STR8## wherein Ph is a phenyl group, in comparisonto the process of the prior art, provide a greatly increased diastereoselectivity with, at the same time, good yield in the invention process.

The (-)-DIOP ligand is the preferred DIOP ligand. The (S,S)-PNNP ligandis the preferred PNNP ligand. Both DIOP and PNNP ligands are known inthe literature, for example:

T. P. Danq et al., J. Chem. Soc. Chem. Commun., (1971), 481, (DIOP).

M. Fiorini et al., J. Mol. Catal., 5, (1979), 303 and J. Mol. Catal., 7,(1980), 411, (PNNP).

As Rh complexes those of the general formula:

    Rh(O): [Rh(L)A].sub.2                                      V

or

    Rh(+): [Rh(L).sub.2 ]B.sup.-                               VI

wherein L stands for two C₂ -C₁₂ olefins (one double bond) or a C₅ -C₁₂-diene, A is a halogen and B⁻ means an anion of an oxygen acid orcomplex acid, are used. L, when it means olefin, preferably contains 2to 6 C atoms and when it means diene, preferably contains 5 to 8 Catoms. In this way the diene can be open-chained, monocyclic orbicyclic. Examples of the olefins are ethylene, propene and 1-butene.Examples of the dienes are 1,5-hexadiene, 1,4-cyclohexadiene, 1,4- or1,5-heptadiene, 1,4- or 1,5-cycloheptadiene, 1,4- or 1,5-octadiene, 1,4-or 1,5-cyclooctadiene, and norbornadiene. Preferably L is two ethylenes,1,5-hexadiene, 1,5-cyclooctadiene or norbornadiene. A preferably ischlorine or bromine. Examples of B⁻ are ClO₄ ⁻, FSO₃ ⁻, CH₃ SO₃ ⁻, CF₃SO₃ ⁻, BF₄ ⁻, PF₆ ⁻, SbCl₆ ⁻, AsF₆ ⁻ and SbF₆ ⁻. Preferably B⁻ is BF₄ ⁻,ClO₄ ⁻, PF₆ ⁻, CF₃ SO₃ ⁻ or SbF₆ ⁻.

The production of these Rh complexes is known and is disclosed, forexample, in J. Chatt et al., J. Chem. Soc., (1957), 4735, and G.Giordano et al., Inorg. Synth., 19, (1979), 218.

The production of the active homogeneous catalyst suitably takes placein situ, i.e., in the context of the hydrogenation of the respectivedihydrofuroimidazole of the general formula I. Suitably the procedure isthat first the homogeneous catalyst components, i.e., the Rh complex andthe corresponding phosphine ligand, are introduced together with thecorresponding dihydrofuroimidazole derivative in a suitable inertsolvent. With attention being paid to appropriate precautions, thereaction is advantageously performed in an oxygen-free inert gasatmosphere.

As the suitable inert solvents that can be used by themselves or inmixture, aprotic solvents, such as, aliphatic and aromatic hydrocarbons,and halogenated hydrocarbons, are suitable. Suitable representatives ofthe aromatic hydrocarbons solvents are, e.g., benzene, toluene andxylene, the aliphatic hydrocarbons are, e.g., hexane and pentane, andthe halogenated hydrocarbons are, e.g., methylene chloride orchloroform. An especially suitable solvent is toluene. It can possiblybe of advantage to use a mixture of one of the mentioned aproticsolvents with a protic solvent such as, the aliphatic alcohols. Methanolis an especially suitable aliphatic alcohol solvent.

The amount of the solvent is suitably selected so that a substrateconcentration of 2 to 30 percent is obtained. Preferably the process iscarried out at a substrate concentration of about 10 percent. The amountof the catalyst, expressed as a ratio of the substrate(dihydrofuroimidazole) to the catalyst, suitably ranges between 100:1and 5000:1, preferably in the amount of about 500:1. The reaction takesplace advantageously at a hydrogen pressure between 1 and 200 bars,preferably 1 to 20 bars and at a reaction temperature between 250 and150° C., preferably between 40° C. and 90° C.

After the hydrogenation, the desired diastereomeric(3aS-6aR)-tetrahydrofuroimidazole of general formula II can be isolatedin a way known to one skilled in the art. Possible parts of the unwanted(3aR-6aS)-tetrahydrofuroimidazole can be removed by recrystallizationwith a suitable solvent, such as, methylisobutyl ketone, ethyl acetateor toluene.

The resulting tetrahydrofuroimidazoles then can be further reacted tothe (+) biotin, for example, according to Europen Published PatentApplication No. 273,270 and U.S. Pat. Nos. 5,162,540 and 4,876,350. Inthe last step in the production process of (+)-biotin disclosed in thesepatents, the protective groups can be cleaved off (which illustrateswhat is meant herein by protective groups which are cleavable in a knownway. For example, the protective groups can be cleaved off by treatmentwith methanesulfonic acid with heating according to teachings ofJapanese Patent Publication Nos. 31669/1970 and 27279/1978.

The invention includes the tetrahydrofuroimidazole derivatives of thegeneral formula II wherein R₁ is a phenyl(C₁ -C₆)-alkyl group, whosearomatic nucleus is substituted with one or more substituents from thelisting composed of (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, hydroxy, a halogen,amino, (C₁ -C₆)-alkylamino, and (C₁ -C₆)-dialkylamino, or wherein R₁ isnaphthyl-(C₁ -C₆)-alkyl that is optionally substituted with one or moreof the afore-mentioned substituents, and R₂ is hydrogen or a protectivegroup which is cleavable in a known way (for example, (C₁-C₆)-alkanoyls, (C₁ -C₆) alkoxy-(C₁ -C₆)-alkyls, (C₁-C₆)-alkoxycarbonyls, aroyls and benzyl; and the aromatic nuclei of therespective groups are optionally substituted with one or moresubstituents of the following: (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, hydroxy,halo, amino, (C₁ -C₆)-alkylamino and (C₁ -C₆)-dialkylamino). Thesecompounds are not known in the literature. Preferably, in these newcompounds, R₁ is an (R) or (S)-1-phenylethyl group whose aromaticnucleus is substituted with one or more of the above-mentionedsubstituents, or is an (R) or (S)-1-naphthylethyl group.

EXAMPLE 1

Production of (3aS,6aR)-tetrahydro-1-[(R)-1-phenylethyl]furo[3,4-d]imidazole-2,4-dione

Under exclusion of oxygen, an autoclave was provided with 3.4 g of3,6-dihydro-l-[(R)-1-phenylethyl]-1H-furo[3,4-d](1,5-imidazole-2,4-dione,13.7 mg of chloro rhodium cyclooctadiene)-dimer and 27.9 mg of (-)-DIOP.After flushing with argon, 75 ml of oxygen-free toluene was added. Thereaction was allowed to proceed for 4 hours at an H₂ pressure of 14 barsand a temperature of 90° C. Afterwards, the HPLC analysis showed a 98percent conversion and a diastereo selectivity (de) of 54 percentrelative to the desired RRS isomer. The autoclave pressure was releasedand it was flushed with nitrogen. The reaction mixture was filtered. Thecrude product was recrystallized in ethyl acetate. 2.25 g (65 percent)of the pure title product was obtained. The product had a melting pointof 156° to 158° C. Other data for the product was:

[α]₅₄₆ +253° C. (C=1.0 CHCl₃)

EXAMPLE 2

Production of(3aS,6aR)-tetrahydro-1-[(R)-1-phenylethyl]furo[3,4-d]imidazole-2,4-dione

Under exclusion of oxygen an autoclave was provided with 3.4 g of3,6-dihydro-1-[(R)-1-phenylethyl]-1H-furo[3,4-d]imidazole-2,4-dione,13.7 mg of chloro rhodium (1,5-cyclooctadiene)-dimer and 27.9 mg of(S,S)-PNNP. After flushing with argon, 75 ml of oxygen-free toluene wasadded. The reaction was allowed to proceed for 4 hours at an H₂ pressureof 14 bars and a temperature of 90° C. Afterwards, the HPLC analysisshowed a 98 percent conversion and a diastereo selectivity (de) of 54percent relative to the desired RRS isomer. The autoclave pressure wasreleased and it was flushed with nitrogen. The reaction mixture wasfiltered. The crude product was recrystallized in ethyl acetate. 2.3 g(67 percent) of the pure title product was obtained. The product had amelting point of 157° to 158° C. Other data for the product was:

[α]₅₄₆ +254° C. (C=1.0 CHCl₃)

EXAMPLE 3

Production of (3aS, 6aR)-3-benzyltetrahydro-1-[(R)-1phenylethyl]furo[3,4-d]imidazo! e-2,4-dione

The reaction took place basically according to Example 1. The molarratio of feedstock/catalyst was 500/1. The reaction was allowed toproceed for 60 hours at 70° C. and an H₂ pressure of 50 bars. A de of 50percent was obtained. Other data for the product Was:

¹ H-NMR (CDCl₃, 400 MHz) δ in ppm 1.57 (d, 3H, J=7.1 Hz); 5.34 (q, 1H)5.03 (d, 1H, J=14.8 Hz); 4.32 (d, 1H); 3.89 (d, 1H, J=9.2 Hz); 4.35 (m,1H, J=5.7 Hz); 3.82 (dd, 1H, J=2.7 Hz); 3.38 (df, 1H, J=10.4 Hz);7.3-7.4 (m, 10H).

EXAMPLE 4

Production of (3as, 6aR)-tetrahydro-1-(2-methoxybenzyl) furo[3,4-d]imidazole-2,4-dione

The reaction took place basically according to Example 1. The molarratio of feedstock/catalyst was 250/1. The reaction was allowed toproceed for 18 hours at 70° C. and an H₂ pressure of 75 bars. A de of 60percent was obtained. Other data for the product was:

¹ H-NMR (CDCl₃, 400 MHz) δ in ppm 3.84 (s, 3H); 4.12 (d, 1H, J=7.7 Hz);4.25-4.35 (m, 3H); 4.45 (d, 1H, J=10.1 Hz); 4.64 (d, 1H, FJ=14.8 Hz);5.63 (s, 1H); 6.89 (d, 1H, J=8.1 Hz); 6.95 (t, 1H, J=7.5 Hz); 7.27-7.32(m, 2H).

EXAMPLE 5

Production of . (3aS, 6aR)-tetrahydro-1-[(R)-1-(2-methoxyphenyl)ethyl]furo[3,4-d]imidazole-2,4-dione

The reaction took place basically according to Example 1. The molarratio of feedstock/catalyst was 130/1. The reaction was allowed toproceed for 18 hours at 70° C. and an H₂ pressure of 85 bars. A de of 50percent was obtained. Other data for the product was:

¹ H-NMR (DMSO-d₆, 400 MHz) δ in ppm 1.59 (d, 3H, J=7.5 Hz); 3.59 (d, 1H,J=11 Hz); 3.35 (s, 3H); 3.95 (dd, 1H, J=11+5 Hz); 4.17 (d, 1H, J=9 Hz);4.53 (m, 1H); 5.42 (s, 1H); 5.43 (q, 1H); 6.91 (d, 1H, J=8 Hz); 6.98 (t,1H, J=7 Hz); 7.25-7.40 (m, 1H).

EXAMPLE 6

Production of(3aS,6aR)-3-acetyltetrahydro-1-[(R)-1-phenylethyl]furo[3,4-d]imidazole-2,4-dione

The reaction took place basically according to Example 1. The molarratio of feedstock/catalyst was 500/1. The reaction was allowed toproceed for 60 hours at 70° C. and an H₂ pressure of 30 bars. A de of 33percent was obtained. Other data for the product was:

¹ H-NMR (CDCl₃, 400 MHz) δ in ppm 1.65 (d, 3H, J=6.5 Hz); 2.55 (s, 3H);3.57 (d, 1H, J=10 Hz); 4.08 (dd, 1H, J=4.0 Hz); 4.58 (dd, 1H, J=9 Hz);5.27 (d, 1H, J=9 Hz); 5.30 (m, 1H).

EXAMPLE 7

Production of (3aS, 6aR)-1-benzyltetrahydrofuro[3,4-d]imidazole-2,4-dione

The reaction took place basically according to Example 1. The molarratio of feedstock/catalyst was 500/1. The reaction was allowed toproceed for 48 hours at 70° C. and an H₂ pressure of 30 bars. A de of 50percent was obtained. Other data for the product was:

¹ H-NMR (CDCl₃, 400 MHz) δ in ppm 4.19 (d, 1H, J=8.0 Hz); 4.25-4.32 (m,4H); 4.68 (d, 1H, J=15.2 Hz); 5.19 (s, 1H); 7.24-7.39 (m, 5H).

EXAMPLE 8

Production of (3aS, 6aR)-tetrahydro-1- [(R)-1-naphthalin-1-ylethyl]furo[3,4-d]imidazole-2,4-dione

The reaction took place basically according to Example 1. The molarratio of feedstock/catalyst was 125/1. The reaction was allowed toproceed for 18 hours at 70° C. and an H₂ pressure of 75 bars. A de of 72percent was obtained. Other data for the product was: ¹ H-NMR (CDCl₃,400 MHz) δ in ppm 1.70 (d, 3H, J=7.5 Hz); 2.66 (d, 1H, J=11 Hz); 3.56(dd, 1H, J=11+5 Hz); 4.20 (d, 1H, J=9 Hz); 4.53 (m, 1H); 5.67 (s, 1H);6.0s (q, 1H); 7.15-8.25 (m, 7H).

What is claimed:
 1. A process comprising asymmetric hydrogenating adihydrofuroimidazole derivative of formula: ##STR9## wherein R₁ is acleavable protective group and R₂ is a hydrogen or a cleavableprotective group, with hydrogen in the presence of a homogeneouscatalyst to the corresponding diastereomeric tetrahydrofuroimidazolederivative of formula: ##STR10## wherein R₁ and R₂ have theafore-mentioned meanings, the homogeneous catalyst being obtained byreaction of an Rh complex with a chiral phosphine ligand from the groupconsisting of: ##STR11## wherein Ph is a phenyl group.
 2. A processcomprising asymmetric hydrogenating a dihydrofuroimidazole derivative offormula: ##STR12## wherein R₁ is a cleavable protective group which isselected from the group consisting of (i) phenyl-(C₁ -C₆)-alkyl, (ii)benzyl and (iii) naphthyl-(C₁ -C₆)-alkyl, each of the aromatic nuclei ofthe groups (i), (ii) and (iii) being unsubstituted except as defined orbeing substituted with one or more substituents selected from the groupconsisting of (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, hydroxy, halo, amino, (C₁-C₆)-alkylamino and (C₁ -C₆)-dialkylamino, and R₂ is a hydrogen or acleavable protective group which is selected from the group consistingof (a) (C₁ -C₆)-alkanoyl, (b) (C₁ -C₆)-alkoxy-(C₁ -C₆)-alkyl, (c) (C₁-C₆)-alkoxycarbonyl, (d) aroyl and (e) benzyl, each of the aromaticnuclei of the groups (a), (b), (c), (d) and (e) being unsubstitutedexcept as defined or being substituted with one or more substituentsselected from the group consisting of (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy,hydroxy, halo, amino, (C₁ -C₆)-alkylamino and (C₁ -C₆)-dialkylamino,with hydrogen in the presence of a homogeneous catalyst to thecorresponding diastereomeric tetrahydrofuroimidazole derivative offormula: ##STR13## wherein R₁ and R₂ have the afore-mentioned meanings,the homogeneous catalyst being obtained by reaction of an Rh complexwith a chiral phosphine ligand from the group consisting of: ##STR14##wherein Ph is a phenyl group, the reaction taking place at a hydrogenpressure of 1 to 200 bars and a reaction temperature of 25° to 150° C.,and the amount of the homogeneous catalyst, expressed as a ratio of thedihydrofuroimidazole to the homogeneous catalyst, being between 100:1 to5000:1.
 3. The process according to claim 1, wherein the (-)-DIOP ligandor the (S,S)-PNNP ligand is used as the chiral phosphine ligand.
 4. Theprocess according to claim 3 wherein a Rh complex of formula:

    Rh(O):[Rh(L)A].sub.2                                       V

of

    Rh(+):[Rh(L).sub.2 ]B.sup.-                                VI

wherein L is two C₂ -C₁₂ olefins or a C₅ -C₁₂ -diene, A is a halogen andB⁻ is an anion of an oxygen acid or complex acid, is used.
 5. Theprocess according to claim 4 wherein an aprotic solvent is presentduring the reaction.
 6. The process according to claim 5 wherein theaprotic solvent is toluene.
 7. The process according to claim 2 whereina Rh complex of formula:

    Rh(O):[Rh(L)A].sub.2                                       V

or

    Rh(+):[Rh(L).sub.2 ]B.sup.-                                V

wherein L is two C₂ -C₁₂ olefins or a C₅ -C₁₂ -diene, A is a halogen andB⁻ is an anion of an oxygen acid or complex acid, is used.
 8. Theprocess according to claim 2 wherein an aprotic solvent is presentduring the reaction.
 9. The bprocess according to claim 8 wherein theaprotic solvent is toluene.